This invention relates to a process for resolution of racemic mixtures of substituted alkanoic acids. More specifically, the process of this invention relates to resolution of acylated D,L-alkyl substituted alkanoic acids useful as intermediates in the preparation of useful pharmaceutical products.
Resolution of racemic mixtures of optically active components was a problem faced by early chemists and is still with us today. Although significant progress continues to be made and new resolving agents and techniques are applied, it is still not today possible to carry out resolutions of organic compounds bearing functional groups quite rationally and with a high probability of success without the use of a systematic approach, a reasonably large collection of resolving agents and an understanding of phase and solubility behavior of stereoisomers to guide one during resolutions. Thus, occasionally the successful resolution of even simple organic compounds is difficult to achieve and in many cases such resolutions are often tedious. For this reason, many experienced investigators in the field of organic chemistry continue to view resolutions as an art, Wilen et al, Tetrahedron, Vol. 33, pp. 2725 et seq., Pergamon Press, Great Britain, 1977.
Of chief importance in the resolution of optically active enantiomers is the selection of a good resolving agent. The criteria involved include the following factors. (1) The compound between the resolving agent and the substance to be resolved should be easily formed and should also be easily broken up, for once one of the diastereoisomers is obtained in the pure state, it must be decomposed chemically so that the pure optically active material may be recovered. (2) The compound between the resolving agent and the substance to be resolved must be nicely crystalline, and there must be an appreciable difference in solubility between the compound formed by the resolving agent and the substance to be resolved. (3) The resolving agent must be either cheap or readily prepared or else readily and nearly quantitatively recoverable after completion of the resolution. If not, large scale resolutions become excessively tedious or expensive, Eliel, Stereochemistry of Carbon Compounds, pp. 49-51, McGraw-Hill, New York, N.Y. 1962.
In principle, all methods of resolution depend on one or the other of two facts: (1) that the products formed by the interaction of two enantiomers with a chiral reagent will be diastereomerically related and will therefore be susceptible to separation by conventional physical methods such as fractional crystallization, distillation, extraction, column chromatography or gas-liquid chromatography so that resolution is achieved if the desired enantiomers can be individually regenerated from the separated diastereomers, and (2) that enantiomers react at different rates with a chiral reagent so that when a pair of enantiomers interacts with a chiral reagent the transition states of the interaction are no longer mirror images of each other; thus, these transition states are diastereomeric rather than enantiomeric and will differ in, amongst other properties, internal energy. It follows that the activation energy for reaction of the enantiomers with a chiral reagent will be different and hence the difference in rates of reaction. Kinetic methods of resolution exploit this difference, Boyle, Quarterly Reviews 25, pp. 323-326, 1971.
The present invention takes advantage of the diastereomeric properties and seeks to separate the resultant diastereomers by crystallization.